PROJECT SUMMARY Colorectal cancer (CRC) is the third-leading malignancy in the United States. This year more than 150,000 cases of colorectal cancer will be diagnosed and more than 50,000 people will die from the disease (http://ser.cancer.gov/cgi-bin/csr/). Consequently there is an unmet medical need for new methods for treating and preventing CRC. Bile acids, which are elevated in individuals with high fat diets, were recognized as risk factors for colorectal cancer more than 30 years ago. Paradoxically, ursodeoxycholic acid, a bile acid that is not natural to humans but which is derived from the bear, has actually shown chemopreventative properties for colorectal cancer. Despite the link between natural bile acids and colorectal cancer, and the unusual chemopreventative properties of ursodeoxycholic acid (UDCA), the mechanistic connections between bile acids and colorectal cancer remain poorly defined. The proposed study focuses on the farnesoid X receptor a (FXRa), a member of the nuclear receptor family of transcription factors that is expressed in the intestinal tract. This receptor is activated by bile acids, and regulates the expression of target genes involved in bile acid homeostasis and cell differentiation. The primary hypothesis of this study is that the FXRa signaling pathway is a valid target for chemoprevention in colorectal cancer. We have found that reduction of FXRa promotes tumorigenesis in a two independent mouse models of colorectal cancer. Moreover, we have found that ileal bile acid binding protein (IBABP) operates in a positive feedback loop with FXR and is necessary for FXR activity, thus factors that influence IBABP are likely to alter the function of FXR and therefore impact tumor incidence and growth. We also have evidence indicating that UDCA forms a complex with IBABP, which then stimulates FXRa. Together these results suggest that there are two routes to targeting the FXR pathway for chemoprevention: hitting FXR directly or by increasing FXR activity through IBABP. To test our hypothesis, we will address the following questions: 1) Does FXRa have a role in protecting the intestine from tumorigenesis? 2) When is FXRa therapy suitable for prevention of CRC? 3) Can small molecule agonists of FXRa prevent CRC? 4) Are the chemopreventative properties of UDCA a result of its binding to IBABP and the corresponding transactivation of FXRa? 5) Is the single nucleotide polymorphism of IBABP associated with the development of CRC and the response to UDCA? Results from this study are likely to provide new methods for chemoprevention, and novel assays for identifying responsive sub-populations.